Oxazoline mediated routes to a unique amino-acid, 4-amino-13-carboxy[2.2]paracyclophane, of planar chirality

Article abstract of DOI:10.1016/S0040-4020(00)00644-X

Efficient syntheses leading to 4-amino-13-carboxy[2.2]paracyclophane and derivatives are described. Novel oxazolinyl[2.2]paracyclophanes are used as intermediates and the oxazolinyl and amide groups are shown to be strong ψ-geminal directing groups. Compounds with potential as catalysts have been made. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00644-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7331–7338
Oxazoline Mediated Routes to a Unique Amino-acid,
4-Amino-13-carboxy[2.2]paracyclophane, of Planar Chirality
a,b
Anne Marchand,a Anderson Maxwell,b Baldwin Mootoo,b Andrew Peltera, and Alicia Reid
*
aDepartment of Chemistry, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
bDepartment of Chemistry, University of the West Indies, St. Augustine, Trinidad and Tobago
Received 24 May 2000; revised 4 July 2000; accepted 13 July 2000
Abstract—Efficient syntheses leading to 4-amino-13-carboxy[2.2]paracyclophane and derivatives are described. Novel oxazolinyl[2.2]-
paracyclophanes are used as intermediates and the oxazolinyl and amide groups are shown to be strong c-geminal directing groups.
Compounds with potential as catalysts have been made. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
As part of a programme directed to the investigation of uses
of [2.2]paracyclophanes in chiral synthesis,1,2,3 we are
attempting to synthesise unique, homochiral amino-acids 1
which owe their chirality to the planar chirality4 of unsym-
metrical [2.2]paracyclophanes. We have succeeded in
producing homochiral 2 and 31,2 (1, nˆmˆ0) from which
our calculations indicate that conformationally constrained
peptide chains with artificial b-sheet structures could be
grown.5,6 The [2.2]paracyclophane moiety would be acting
as a rigid, lipophilic b-turn mimetic.7,8,9
Our previous synthesis of 2 and 3 involved the nitration of
homochiral, readily available 4-carbomethoxy[2.2]para-
cyclophane2 followed by hydrolysis and reduction. The
latter two steps both went in Ͼ80% yields but the nitration
gave only 37% of mono-nitrated material from which 13-
carbomethoxy-4-nitro[2.2]paracyclophane,† the precursor
of 2, was isolated in 15% yield and 12-carbomethoxy-4-
nitro[2.2]paracyclophane, the precursor of 3 was isolated
in 8% yield. This is in line with the nitration of [2.2]para-
cyclophane itself which, in our hands, gave only 12% of
4-nitro[2.2]paracyclophane.10,11,18
We therefore designed several approaches to 2, one of
which involving oxazolines is described below. We felt
that oxazolines would be useful for the following reasons.
The first is that 2 is c-geminally (4,13) disubstituted and
therefore a c-geminal reaction must, at some stage, be
carried out. c-Geminal directing groups are normally
ester, carboxylic acid or ketone groups in which the
carbonyl group can act as an intramolecular base to prefer-
entially abstract a proton from C-13 of the carbocation
complex involved in electrophilic bromination of the
adjacent ring.12 At some later stage in the synthesis we
anticipated the use of organolithium or organomagnesium
reagents and therefore the acid or ester group would have to
be protected. An oxazoline ring seemed ideal for this
purpose.13 Moreover homochiral 4-carboxy[2.2]paracyclo-
phane 4 is readily available11,15–17 as is its methyl ester 5,
which we have already used in the synthesis of homochiral
2 and 3.2 Therefore any synthesis that proceeds through 4
or 5 must be considered as a potential chiral synthesis and
this strongly influenced our approach. As a result we investi-
gated Scheme 1, in which the required 4,13-substitution
Keywords: 4-amino-13-carboxy[2.2]paracyclophane; planar chirality;
oxazolines; directing effects; potential catalysts.
* Corresponding author. Tel.: ϩ44-1792-295258; fax: ϩ44-1792-295747;
e-mail: a.pelter@swansea.ac.uk
†
All bifunctional [2.2]paracyclophane derivatives described in the Experi-
mental and text are numbered as for 2.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00644-X

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A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
Scheme 1. Reagents i, Br2/Fe, 6 to 7 (93%), 5 to 8 (87%); ii, Mg then ClCO2Me (80%), iii, aq. KOH (80%); iv, SOCl2 then NH2CMe2CH2OH (69%); v, NEt3/
PPh3/CCl4 (97%). ءThis numbering is used for mono-substituted [2.2]paracyclophane derivatives.
Scheme 2. Reagents i, Mg then CO2 (97%); ii, SOCl2 then NH2CMe2CH2OH (94%); iii, Br2/Fe 12 to 10 (100%), 13 to 11 (92%); iv, NEt3/PPh3/CCl4, 10 to 11
(97%), 12 to 13 (95%).

A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
7333
Scheme 3. Reagents i, nBuLi, -78ЊC (100%), ii, CO2 then aq. acid (100%); iii, (a) SOCl2, (b) NaN3/acetone (c) toluene, heat, (d) aq.KOH (58%); iv, 6 M HCl;
(100%); v, conc. HCl then MeOH, heat (78%).
pattern is introduced by the known, high yield bromination
of 5.12 For this initial investigation we used racemic
compounds.
phane 6 in 82% overall yield and 11 must now therefore be
regarded as readily available.
Alternatively 12 was converted to 13 in 92% yield and 13 on
bromination gave 11 in 95% yield. By this route 11 was
made from 5 in an overall yield of 74%.
The bromination of 6 to 7 is known and direct conversion of
7 to 5 proceeded in excellent yield.18 c-Geminal bromina-
tion to give 8 (87%) was followed by hydrolysis to give 9
(80%). The conversion of 9 to 10 was somewhat disappoint-
ing as, despite various attempts, it proceeded at best in 69%
yield only. The overall yield from 6 to 10 was 36%.
Thus both amide and oxazolinyl groups are new c-geminal
directing groups. Oxazolines 11 and 13 are the first
4-[2,2]paracyclophanyloxazolines.
The next step was the preparation of 11, a key intermediate.
We had originally intended to convert ester 8 directly to 11
but although we managed to quantitatively convert methyl
benzoate to 2-phenyl-4,4-dimethyloxazoline using potas-
sium hydroxide as base, the reaction failed on ester 8. We
therefore considered the conversion of 10 to 11. We
investigated a large number of methods13 for this conversion
but found that Bryce’s method14 gave the highest yield
(97%). A convenient and cheaper alternative was the use
of cold thionyl chloride which gave an excellent yield in the
conversion of 12 to the corresponding oxazoline. Although
11 did become available by this process the overall yield
was only 35% and we looked for alternatives.
As expected 11 yielded the lithio-derivative 14 in quanti-
tative yield with no interference from the oxazoline ring
(Scheme 3). We attempted to convert 14 directly to 15 by
the method of Fringuelli19 using O-methylhydroxylamine.
However although on one occasion we obtained 60% of 15
the reaction was inconsistent and generally gave yields of
Ͻ20%. We therefore converted 14 into the carboxylic acid
16 and used a Curtius process to consistently give 15 in 58%
overall yield. Compound 15 is a most interesting masked
form of 2 which is ready for peptide growth from the amine
group. Treatment of 15 with 6 M HCl gave a quantitative
yield of the required amino-acid 2. The methyl ester 17 was
also available directly from 15.
On consideration it seemed reasonable that both amides and
oxazolines could be c-geminal directing groups and, if so,
this opened up the two routes shown in Scheme 2.
The target amino acid 2 is thus available from [2.2]para-
cyclophane in 48% overall yield.
Oxazoline 11 is of great interest apart from its conversion to
2. Scheme 4 shows its conversions (unoptimised) to two
compounds, 18 and 19 with liganding groups held rigidly
in close proximity. The possibilities of using 19 as a ligand
in a variety of transition metal catalysed reactions are
currently under investigation.
Compound 12 was produced in high yield from 4 and on
bromination gave a quantitative yield of the c-geminal
product 10. Cyclisation of 10 to 8 had already been shown
to proceed in 97% yield (Scheme 1). By this route
compound 11 is produced from the parent [2.2]paracyclo-

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A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
Scheme 4. Reagents i, nBuLi, Ϫ78ЊC, PhSSO2Ph (52%); ii, nBuLi, Ϫ78ЊC, ClPPh2 (56%).
Experimental
magnesium turnings (1.87 g, 76.82 mmol). A crystal of
iodine was added and the turnings stirred and heated with
a hot air gun for 1 h after which 4-bromo[2.2]paracyclo-
phane 7 (20 g, 69.69 mmol) in THF (90 ml) was added
slowly over 1 h and the mixture was then stirred for a further
4 h. The Grignard solution was cooled to 0ЊC and then
added, using a double ended needle, to a stirred solution
of methyl chloroformate (33 ml, 431.2 mmol) in THF
(100 ml) also at 0ЊC and then stirred overnight at room
temperature. The pale yellow mixture was concentrated
and the residue was dissolved in dichloromethane and
washed with brine. The organic layer was separated, dried
(MgSO4) filtered and concentrated. The pale yellow residue
was purified by chromatography on silica (petroleum ether:
CH2Cl2, 90:10 then 50:50) followed by crystallisation from
CH2Cl2:Et2O (20:80) to give 5, (14.82 g, 80%) mp 135–
137ЊC (lit.21 139–140ЊC). The 1H and 13C NMR mass
spectrum and UV spectra were identical with a sample
previously made18 from the corresponding acid.
General information
Melting points were determined using an Electrothermal
digital melting point apparatus. Microanalyses were carried
out at the University of Wales Cardiff. IR spectra were
1
recorded on a Pye Unicam SP1050 spectrometer. H NMR
spectra were recorded on a Bruker 250WM spectrometer at
250 MHz or on a Bruker ARX400 spectrometer at
400 MHz. 13C NMR spectra were recorded on a Bruker
ARX400 spectrometer at 100 MHz. All NMR spectra used
tetramethylsilane as the internal standard and were run in
CDCl3 unless otherwise stated. J values are given in Hz. The
mass spectra were obtained from a VG-12-250 low resolu-
tion quadrupole mass spectrometer, whilst accurate mass
measurements were obtained from a ZAB-E, high resolu-
tion, double focussing mass spectrometer. UV spectra were
recorded on a Philips PU8720 scanning spectrometer and
reported in nm (e). Thin layer chromatography (TLC) was
carried out on Merck 5735 Kieselgel 60 F254 fluorescent
plates. Flash chromatography was performed with silica
gel (Merck Geduran SI 60 Art 11567).
4-Bromo-N-(1-hydroxy-2-methyl-2-propyl)[2.2]paracyclo-
phane-13-carboxamide 10. (i) Thionyl chloride (2 ml,
27.4 mmol) was added to 9 (1 g, 3 mmol) at room tempera-
ture and the mixture stirred at room temperature for 30 min
and then at 60ЊC for 1.5 h. The cooled mixture was concen-
trated and then three portions of toluene were added sequen-
tially, each being taken to dryness. The resulting solid was
taken into dichloromethane (10 ml), cooled to 0ЊC and to the
resulting solution was added a solution of 2-amino-2-
methylpropan-1-ol (0.58 ml, 6 mmol) and triethylamine
(0.84 ml, 6 mmol) in dichloromethane (10 ml) dropwise
over 45 min. The reaction mixture was allowed to warm
to room temperature and stirred overnight. Dichloro-
methane (50 ml) was added and the solution washed with
4% aqueous NaHCO3 (2×50 ml) and brine (50 ml), dried
(MgSO4), filtered and concentrated. Purification by flash
chromatography (silica, petroleum ether/ethyl acetate
60:40) gave 10 as a white solid (0.84 g, 69%) mp 169–
170ЊC.
Reactions carried out under an inert atmosphere refer to the
use of argon or nitrogen. Ether, tetrahydrofuran (THF) and
benzene were dried by being stirred overnight over calcium
hydride, distilled and then distilled again from sodium wire
and benzophenone. Dichloromethane, toluene, acetone and
carbon tetrachloride were dried by distillation from calcium
hydride after stirring overnight with CaH2. Solutions of
butyllithium in hexane and methyllithium in ether were
obtained from Aldrich and were regularly estimated.20
Low temperature baths were prepared by making a slurry
of solid carbon dioxide with acetone (Ϫ78ЊC). All other
reagents were purified by distillation, the pressure being
reduced if the boiling point of the compound was greater
than 110ЊC at atmospheric pressure.
Direct preparation of 4-carbomethoxy[2.2]para-
,‡
cyclophane 518
(ii) A solution of bromine (1.15 ml, 22.3 mmol) in dichloro-
methane (240 ml) was made up and 20 ml added to iron
powder (0.12 g, 2.16 mmol) with exclusion of light. The
mixture was stirred for 1 h and 12 (6 g, 18.6 mmol) in
dichloromethane (360 ml) was added rapidly, with stirring.
The resulting mixture was heated under reflux, the remain-
der of the bromine solution added dropwise over 2 h and
A dry, three-necked round bottomed flask fitted with a dry
dropping funnel and condenser was charged with dry
‡
We thank Mr H. Kidwell (University of Wales Swansea) who first intro-
duced this procedure.

A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
7335
the solution heated under reflux for 18 h. The reaction
mixture was cooled, washed with saturated aq. NaHCO3
(2×500 ml) and brine (500 ml) and the organic layer dried
(MgSO4), filtered and concentrated to give almost pure 10 in
quantitative yield. Purification by flash chromatography
(silica, petroleum ether:ethyl acetate, 60:40) gave 10 as a
white solid (7.07 g, 95%) mp 169–170ЊC. dH 1.36 (3H, s,
CH3), 1.46 (3H, s, CH3), 2.87 (1H, ddd, Jˆ6.5, 10.0,
13.5 Hz, H-2a), 3.07 (5H, m, H-1b, 9a, 9b, 10a, 10b), 3.56
(1H, ddd, Jˆ2.0, 9.5, 13.5 Hz, H-2b), 3.68 (2H, d,
Jˆ5.5 Hz, CH2OH), 3.94 (1H, ddd, 6.5, 9.5, 13.5 Hz, H-
1a), 5.32 (1H, t, Jˆ5.5 Hz, OH), 5.80 (1H, s, NH), 6.57
(5H, m, H-5, 8, 15, 16), 7.11 (1H, d, Jˆ1.7 Hz, H-12). dC
24.4, 25.1 (2×CH3), 31.8, 34.5, 34.9, 36.6 (C-1, 2, 9, 10),
56.6 (C(CH3)2), 71.1 (OCH2), 126.9, 134.7, 137.7, 138.5,
139.2, 141.3 (C-3, 4, 6, 11, 13, 14), 130.8, 131.1, 133.0,
134.9, 135.8, 136.2 (C-5, 7, 8, 12, 15, 16), 168.4
103 (20), 77 (23). HRMS Found: Mˆ383.0885.
C21H22BrNO requires 383.0885.
4-Carboxy[2.2]paracyclophane 4.16 A dry, three-necked
flask fitted with a dropping funnel and a condenser was
charged with some dry magnesium turnings (2.33 g,
95.84 mmol) and the turnings stirred under argon. After
1 h some crystals of iodine were added, the flask warmed
with an air gun and stirring continued for ca. 4 min until
some iodine sublimed. 4-Bromo[2.2]paracyclophane 7
(22.4 g, 78.74 mmol) in dry THF (150 ml) was added drop-
wise over 3 h to the activated magnesium with heating and
stirring. The mixture was heated under reflux for 4 h, the
solution cooled to room temperature and carbon dioxide,
˚
dried on CaCl2, SiO2, 5 A molecular sieves, P2O5 and
sulfuric acid was bubbled through for 18 h. The reaction
mixture was acidified with 6 M HCl to pH 2.5, extracted
with dichloromethane (4×150 ml), and then the combined
organic extract was washed with aq. NaOH (4×175 ml,
12.5 M). The aqueous extract was acidified to pH 2.5 and
gave a white precipitate that was extracted with dichloro-
methane, dried (MgSO4), filtered and concentrated to give
pure 4 (19.29 g, 97%) mp 214–215ЊC (lit.21 210–221Њ), ex
AcOH. The product gave identical 1H and 13C NMR spectra
with an authentic sample and also ran as one peak on
coinjection (HPLC) with an authentic sample. dH 2.90
(1H, ddd, Jˆ7.2, 10.0, 12.7 Hz, H-2b), 3.01 and 3.19 (6H,
2m, H-1a, 1b, 9a, 9b, 10a, 10b), 4.21 (1H, ddd, Jˆ2.5, 8.8,
12.7 Hz, H-2a), 6.51, 6.59 (4H, m, H-12, 13, 15, 16), 6.58
(1H, d, Jˆ7.8 Hz, H-8), 6.71 (1H, dd, Jˆ1.9, 7.8 Hz, H-7),
7.29 (1H, d, Jˆ1.9 Hz, H-5). dC 34.9, 35.1, 35.2, 36.3 (C-1,
2, 9, 10), 129.6 (C-3), 131.8, 132.3, 132.8, 133.1, 136.2,
136.4, 137.4 (C-5, 7, 8, 12, 13, 15, 16), 139.4, 140.0,
140.1 (C-6, 11, 14), 143.7 (C-4), 172.5 (CO2H). lmax
(CH2Cl2) 229.9 (17,680). nmax (cmϪ1) 1685 (CvO), 2852,
2925 (Ar-H).
(CvO). lmax (CH2Cl2) 229.8 (16,242). nmax (cmϪ1
)
1641 (CO), 2926 (OH), 3417 (NH). m/z (EI) 402, 404
(Mϩ, 30), 322 (22), 219 (29), 147 (100), 131 (22), 103 (20),
77 (18). HRMS Found: Mˆ401.0990. C21H24BrNO2
requires 401.0990.
4-Bromo-13-(4,4-dimethyloxazolin-2-yl)[2.2]paracyclo-
phane 11. (i) To a solution of 10 (7 g, 17.41 mmol) in aceto-
nitrile (400 ml) were added sequentially triethylamine
(10.4 ml, 74.81 mmol), triphenylphosphine (16.15 g, 61.15
mmol) and carbon tetrachloride (15.6 ml, 161.4 mmol). The
resultant mixture was stirred under argon at rt for 12 h. The
solution was concentrated then diluted with dichloro-
methane (400 ml) and washed with brine (2×400 ml). The
organic layer was dried (MgSO4), filtered and concentrated.
Purification by flash chromatography gave pure 11 (6.47 g,
97%) as a white solid mp 138–139ЊC.
(ii) c-Geminal bromination of 13 (0.5 g) was accomplished
by the same method as that used to prepare 10. Flash
chromatography of the crude product on silica (petroleum
ether:ethyl acetate, 80:20) as in (i) gave 11 as white crystals
(0.54 g, 85%) mp 138–139ЊC ex petroleum ether:ethyl
acetate 80:20. Found: C, 65.72; H, 5.73; N, 3.71%.
C21H22BrNO requires C, 65.63; H, 5.76; N, 3.64%. dH
1.34 (3H, s, CH3), 1.41 (3H, s, CH3), 2.88 (1H, ddd,
Jˆ4.9, 10.4, 13.3 Hz, H-2a), 2.97 (4H, m, H-9a, 9b, 10a,
10b), 3.03 (1H, ddd, Jˆ3.4, 10.4, 13.4 Hz, H-1b), 3.51 (1H,
ddd, Jˆ3.4, 10.0, 13.4 Hz, H-2b), 4.09 (2H, 2×d, Jˆ7.8 Hz,
OCH2), 4.46 (1H, ddd, Jˆ4.9, 10.0, 13.4 Hz, H-1a), 6.50
(1H, d, Jˆ7.8 Hz, H-15), 6.52 (2H, m, H-7, 8), 6.55 (1H, dd,
Jˆ1.9, 7.8 Hz, H-16), 6.62 (1H, br.s., H-5), 7.19 (1H, d,
Jˆ1.9 Hz, H-12); dH (C6D6) 1.2 (3H, s, CH3), 1.36 (3H, s,
CH3), 2.60 (4H, m, H-9a, 9b, 10a, 10b), 2.69 (1H, ddd,
Jˆ3.9, 10.4, 13.5 Hz, H-2a), 2.83 (1H, ddd, Jˆ4.3, 10.4,
13.2 Hz, H-1b), 3.66 (1H, ddd, Jˆ4.3, 9.8, 13.5 Hz, H-2b),
3.76, 3.86 (2H, 2×d, Jˆ7.8 Hz, OCH2), 4.90 (1H, ddd,
Jˆ3.9, 9.8, 13.2 Hz, H-1a), 6.21 (4H, m, H-7, 8, 15, 16),
6.59 (1H, br.s., H-5), 7.40 (1H, br.s., H-12). dC, 28.0, 28.3
(2CH3), 32.8, 34.4, 34.8, 35.6 (C-1, 2, 9, 10), 67.5
(C(CH3)2), 78.1 (OCH2), 126.8, 127.0 (C-6, 11), 131.3,
131.3, 132.4, 134.7, 135.0, 136.0, 136.1 (C-5, 7, 8, 12, 15,
16), 138.4, 139.0, 140.4, 141.1 (C-3, 4, 13, 14), 161.9
(CvN). lmax (CH2Cl2) 236.0 (13,167). nmax (cmϪ1) 1637
(CvN). m/z (CI) 384, 386 (Mϩ1ϩ, 100), (EI) 383 and 385
(Mϩ, 10), 207 (100), 184 (8), 146 (15), 131 (10), 115 (5),
N-(1-Hydroxy-2-methyl-2-propyl)[2.2]paracyclophane-
4-carboxamide 12. Thionyl chloride (13.5 ml, 0.18 mol)
was added to 4-carboxy[2.2]paracyclophane
4 (8 g,
0.032 mol) at room temperature and the mixture was
brought to 60ЊC and stirred for 4 h. Most of the thionyl
chloride was removed under reduced pressure and the last
traces by azeotropic distillation with three portions of
toluene. The resultant solid was dissolved in dichloro-
methane (60 ml) and cooled to 0ЊC. A cooled mixture of
2-amino-2-methylpropan-1-ol (6.06 ml, 0.0635 mol) and
triethylamine (8.84 ml, 0.0635 mol) was added dropwise
over 3 h. The resulting solution was allowed to warm to
room temperature then stirred overnight. Dichloromethane
(50 ml) was added and the reaction mixture washed with aq.
NaHCO3 (2×100 ml, 3.5%) and then brine (100 ml). The
organic layer was separated, dried (MgSO4), filtered and
concentrated to give pure 12 (9.955 g, 97%), mp 149–
150ЊC (ex petroleum ether:ethyl acetate, 1:1). Found: C,
78.01; H, 7.85; N, 4.20%. C21H25NO2 requires C, 77.98;
H, 7.79; N, 4.33%. dH 1.36 (3H, s, CH3), 1.38 (3H, s,
CH3), 2.88 (1H, ddd, Jˆ6.3, 9.8, 13.0 Hz, H-2b), 3.04
(6H, H-1a, 1b, 9a, 9b, 10a, 10b), 3.59 (1H, ddd, Jˆ3.3,
9.2, 13.0 Hz, H-2a), 3.64 (2H, d, Jˆ6.0 Hz, CH2OH), 5.32
(1H, t, Jˆ6.0 Hz, CH2OH), 5.76 (1H, s, NH), 6.42 (1H, d,
Jˆ7.9 Hz, H-12), 6.46 (1H, d, Jˆ7.8 Hz, H-8), 6.52 (2H, m,
H-15, 16), 6.56 (1H, dd, Jˆ1.8, 7.8 Hz, H-7), 6.64 (1H, d,

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A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
Jˆ1.8 Hz, H-5), 6.76 (1H, d, Jˆ7.9 Hz, H-13). dH (C6D6),
1.15 (3H, s, CH3), 1.17 (3H, s, CH3), 2.67 (1H, ddd, Jˆ5.7,
10.3, 12.7 Hz, H-2b), 2.78 (4H, m, H-9a, 9b, 10a, 10b), 2.92
(1H, ddd, Jˆ1.8, 10.3, 12.7 Hz, H-1a), 3.25 (1H, ddd,
Jˆ5.7, 10.2, 12.7 Hz, H-1b), 3.55 (2H, s, CH2OH), 3.66
(1H, ddd, Jˆ1.8, 10.2, 12.7 Hz, H-2a), 4.62 (1H, br.s.,
CH2OH), 5.41 (1H, br.s., NH), 6.32 (5H, m, H-7, 8, 12,
15, 16), 6.62 (1H, br.s., H-5), 7.04 (1H, br.d., Jˆ8.0 Hz,
H-13). dC 24.5, 24.8 (2×CH3), 34.9, 35.1, 35.3, 35.4 (C-1,
2, 9, 10), 56.4 (C(CH3)2), 71.0 (CH2OH), 131.9, 132.4,
132.5, 132.6, 135.0, 136.0 (C-5, 7, 8, 12, 13, 15, 16),
135.4, 138.5, 139.2, 139.5, 140.3 (C-3, 4, 6, 11, 14) 170.1
(CvO). lmax (CH2Cl2) 230.4 (14,035). nmax (cmϪ1) 1635,
(Cv0) 3392 (NH, OH). m/z (CI) 324 (Mϩ1ϩ), (EI) 323
(Mϩ, 5), 306 (2), 252 (22), 235 (5), 219 (10), 147 (100),
104 (45). HRMS Found: MϩHˆ324.1964. C21H26NO2
requires 324.1964.
phane 16. Carboxylation of 11 (1 g, 2.6 mmol) was accom-
plished by the same method as used for the synthesis of 4. In
the work up acidification was controlled using enough 2N
aq. HCl until the pH was 6.5. The aqueous mixture was then
extracted with dichloromethane (4×100 ml). The organic
layer was dried (MgSO4), filtered and concentrated to give
16 (0.852 g, 94%), mp 180–181ЊC ex light petroleum:ethyl
acetate, 60:40. Found: C, 75.56; H, 6.88; N, 3.98%.
C22H23NO3 requires C, 75.62; H, 6.63; N, 4.01%. dH 1.22
(3H, s, CH3), 1.26 (3H, s, CH3), 3.07 and 4.20 (8H as 2m,
H-1a, 1b, 2a, 2b, 9a, 9b, 10a, 10b), 6.66, 6.67 (2H, 2d,
Jˆ7.7 Hz, H-8, 15), 6.74 (1H, dd, Jˆ1.6, 7.7 Hz, H-7),
7.01 (1H, d, Jˆ1.6 Hz, H-12), 7.37 (1H, d, Jˆ1.6 Hz,
H-5). dC 27.8, 28.1 (2CH3), 34.2, 34.7, 35.0 (C-1, 2, 9,
10), 67.4 (C(CH3)2), 78.3 (OCH2), 128.7, 128.8 (C-6, 11),
132.6 (C-12), 134.8 (C-5), 134.9, 135.5, 136.3, 137.2 (C-7,
8, 15, 16), 139.0, 139.7, 140.7, 144.0 (C-3, 6, 11, 14), 161.8
(CvN), 171.8 (CvO). lmax (CH2Cl2) 245.5 (18, 552). nmax
(cmϪ1) 1635 (CvN), 1681 (CvO), 3469 (CO2H). m/z (CI)
350 (Mϩ1), (EI) 349 (Mϩ, 32), 305 (50), 201 (100), 146
(23), 131 (20), 105 (41). HRMS Found: Mˆ349.1678.
C22H23NO3 requires 349.1678.
4-(4,4-Dimethyloxazolin-2-yl)[2.2]paracyclophane 13. (i)
Cyclisation of 12 (2.4 g, 7.43 mmol) was accomplished by
the same method as for the production of 11. Purification of
the crude product by flash chromatography on silica (eluent
petroleum ether:ethyl acetate, 80:20) gave 13 as a white
solid (2.5 g, 95%), mp 108–109ЊC from the eluent.
Found: C, 82.53; H, 7.77; N, 4.55%. C21H23NO requires
C, 82.58; H, 7.59; N, 4.58%. dH 1.41 (3H, s, CH3), 1.43
(3H, s, CH3), 2.79 (1H, ddd, Jˆ7.0, 10.1, 12.7 Hz, H-2b),
2.97–3.11 (6H, m, H-1a, 1b, 9a, 9b, 10a, 10b), 4.04 (1H, d,
Jˆ7.94 Hz, OCH), 4.06 (H, d, Jˆ 7.94 Hz, OCH), 4.20 (1H,
ddd, Jˆ1.6, 9.8, 12.7 Hz, H-2a), 6.48–6.56 (6H, m, H-7, 8,
12, 13, 15, 16), 7.02 (1H, d, Jˆ1.8 Hz, H-5). dH (C6D6) 1.21
(3H, s, CH3), 1.27 (3H, s, CH3), 2.68 (1H, ddd, Jˆ7.2, 10.1,
12.5 Hz, H-2b), 2.80 (4H, m, H-9a, 9b, 10a, 10b), 3.06 (1H,
ddd, Jˆ1.2, 10.1, 12.7 Hz, H-1a), 3.22 (1H, ddd, Jˆ7.2, 9.9,
12.7 Hz, H-1b), 3.60 (1H, d, Jˆ7.9 Hz, OCH), 3.71 (1H, d,
Jˆ7.9 Hz, OCH), 4.60 (1H, ddd, Jˆ1.2, 9.9, 12.5 Hz,
H-2a), 6.26 (2H, m, H-7, 8), 6.33 (1H, dd, Jˆ1.8, 7.8 Hz,
H-15), 6.40 (1H, dd, Jˆ1.7, 7.8 Hz, H-16), 6.50 (1H, dd,
Jˆ1.7, 7.8 Hz, H-12), 6.80 (1H, dd, Jˆ1.8, 7.8 Hz, H-13),
7.30 (1H, br.s., H-5). dC 28.4 (CH3), 28.5 (CH3), 34.8, 35.0,
35.2, 36.0 (C-1, 2, 9, 10), 67.5 (C(CH3)2), 78.3 (OCH2),
128.5 (C-3), 131.1, 132.2, 132.7, 133.0, 134.3, 134.6,
135.8 (C-5, 7, 8, 12, 13, 15, 16), 139.3, 139.4, 139.8 (C-6,
11, 14), 140.9 (C-4), 162.2 (CvN). lmax (CH2Cl2) 230.4
(15,845). nmax (cmϪ1) 1638 (CvN), 2852–2926 (arom.
C–H). m/z (CI) 306 (Mϩ1ϩ), (EI) 305 (Mϩ, 39), 201
(100), 104 (30). HRMS Found: Mˆ305.1780. C21H23NO
requires 305.1780.
4-Amino-13-(4,4-dimethyloxazolin-2-yl[2.2]paracyclo-
phane 15. Acid 16 (0.352 g, 1.01 mmol) was stirred under
argon with thionyl chloride (0.5 ml, 6.94 mmol) for 4 h at
room temperature. The thionyl chloride was removed and
the residue azeotroped with dry toluene (3×10 ml). The
resulting acid chloride was dissolved in dry acetone
(10 ml) and cooled to 0ЊC. A solution of sodium azide
(0.437 g, 6.72 mmol) in acetone (5 ml) and water (7.5 ml)
was made up and cooled to 0ЊC. The cooled acid chloride
solution was then added to the stirred azide solution by
cannula. The mixture was stirred overnight at room
temperature then extracted with dichloromethane
(4×50 ml). The combined organic layers were concentrated
and the residue was dissolved in toluene (20 ml) and heated
under reflux for 2 h. Aqueous KOH (10 ml 10% w/v) was
added to the boiling toluene solution the mixture then being
heated under reflux for a further 3 h. The mixture was
concentrated and the residue was dissolved in dichloro-
methane (30 ml). The amine was extracted as a salt using
HCl (3×50 ml, 2 M) and the acid solution was then treated
with aqueous KOH to pH 9–10. The product was taken into
dichloromethane (4×60 ml), the solution dried (MgSO4),
filtered and concentrated to give pure 15 (0.1918 g, 59%)
mp 160–161ЊC. dH 1.30 (3H, s, CH3), 1.31 (3H, s, CH3),
2.64 (1H, ddd, Jˆ6.4, 10.6, 16.4 Hz, H-2a), 2.88 (5H,
m, 1b, 9a, 9b, 10a, 10b), 3.06 (1H, m, H-2b), 3.30 (2H,
br, NH2), 3.94 (1H, d, Jˆ8.0 Hz, OCH), 4.00 (1H, d,
Jˆ8.0 Hz, OCH), 4.18 (1H, ddd, Jˆ6.4, 9.4, 16.4 Hz,
H-1a), 5.43 (1H, d, Jˆ1.7 Hz, H-5), 6.01 (1H, dd,
Jˆ1.7, 7.7 Hz, H-7), 6.27 (1H, d, Jˆ7.7 Hz, H-8),
6.31 (1H, d, Jˆ7.7 Hz, H-15), 6.50 (1H, dd, Jˆ1.9,
7.7 Hz, H-16), 7.06 (1H, d, Jˆ1.9 Hz, H-12). dC 28.2
(2×CH3), 30.9, 32.3 (C-1, 2) 34.6, 34.8 (C-9, 10), 67.4
(C(CH3)2), 78.5 (OCH3), 121.4, 122.4 (C-5, 7), 132.2,
134.4 (C-8, 12, 15, 16), 124.2, 125.5 (C-3, 14), 138.3
(C-13), 140.0, 140.6 (C-6, 11), 146.5 (C-4), 163.4
(CvN). lmax (CH2Cl2) 226 (19,192), 249 (12,808). nmax
(cmϪ1) 3418, 3312 (N-H), 1624 (CvN). m/z (EI) 320
(Mϩ, 65), 201 (100), 119 (42). HRMS Found:
Mˆ320.18890. C21H24N2O requires 320.18885.
(ii) Thionyl chloride (2 ml) was distilled from zinc into a dry
round-bottomed flask containing 12 (0.2 g, 0.6191 mmol)
and the mixture was stirred at room temperature for 4 h.
The mixture was concentrated on a rotary evaporator and
the residue dissolved in dichloromethane (30 ml) and
stirred with 20% NaOH (25 ml). The organic layer
was washed with brine (20 ml), separated, dried and
concentrated to give a quantitative yield of product
mp 107–108ЊC, that was 96% pure by HPLC. Crystal-
lisation from petroleum ether:ethyl acetate (80:20) gave
crystals mp 108–109ЊC identical in all respects with the
product from (i).
4-Carboxy-13-(4,4-dimethyloxazolin-2-yl)[2.2]paracyclo-

A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
7337
4-Amino-13-carboxy[2.2]paracyclophane 2.2 Aqueous
HCl (6 ml, 6 M) was added to a flask containing 15
(0.053 g, 0.1654 mmol). The mixture was heated under
reflux for 24 h then cooled to room temperature and aq.
NaOH (40%) was added dropwise to pH 3–5 until the
amino-acid precipitated out. The sparingly soluble precipi-
tate was taken into dichloromethane (5×20 ml), the solvent
concentrated then pumped under high vacuum for 18 h to
give pure (1H NMR, 13C NMR, HPLC) 2, (0.0444 g, 100%)
mpϾ289ЊC decomp. dH (CD3OD) 2.78 (1H, ddd, Jˆ5.0,
10.7, 15.3 Hz, H-2a), 2.89–3.02 (5H, m, H-9a, 9b, 10a,
10b, 1b), 3.07 (1H, m, H-2b), 4.17 (1H, ddd, Jˆ5.0, 9.9,
15.3 Hz, H-1a), 5.65 (1H, d, Jˆ1.7 Hz, H-5), 6.24 (1H, dd,
Jˆ1.7, 7.7 Hz, H-7), 6.40 (1H, d, Jˆ7.7 Hz, H-8), 6.43 (1H,
d, Jˆ7.7 Hz, H-15), 6.67 (1H, dd, Jˆ1.9, 7.7 Hz, H-16),
7.08 (1H, d, Jˆ1.9 Hz, H-12). dC 32.2, 32.4, 35.4, 35.6
(CH2), 123.7, 126.1, 129.5, 127.9, 131.3, 133.8, 136.2,
136.1, 137.0, 140.1, 141.8, 142.1, 174.1 (CvO). m/z (CI)
268 (Mϩ1ϩ, 48) 226 (37), 224 (32). m/z (EI) 267 (Mϩ, 3),
148 (13), 119 (54), 118 (23), 92 (32), 91 (100). HRMS
Found: Mˆ267.1266. C17H17NO2 requires 267.1266.
78.41; H, 6.58; N, 3.38%. dH 1.43 (3H, s, CH3), 1.52 (3H, s,
CH3), 2.79 (1H, ddd, Jˆ4.5, 10.2, 13.6 Hz, H-2a), 3.01 (5H,
m, H-1b, 9a, 9b, 10a, 10b), 3.43 (1H, ddd, Jˆ4.0, 9.9,
13.6 Hz, H-2b), 4.11 (1H, d, Jˆ7.8 Hz, OCH), 4.25 (1H,
d, Jˆ7.8 Hz, OCH), 4.45 (1H, ddd, Jˆ4.5, 9.9, 13.5 Hz,
H-1a), 6.66 (5H, m, H-5, 7, 8, 15, 16), 7.11 (6H, m,
5SArH, H-12). dC 28.0 (CH3), 28.4 (CH3), 33.6, 34.2,
34.5, 34.8 (C-1, 2, 9, 10), 67.6 (C(CH3)2), 78.3 (OCH2),
125.8, 128.2, 128.8, 132.6, 132.9, 134.9, 135.0, 136.0,
136.9 (C-5, 7, 8, 12, 15, 16 and C6H5), 129.0, 135.5,
137.9, 138.6, 140.2, 140.7, 142.4 (C-3, 4, 6, 11, 13, 14),
161.8 (CvN). lmax (CH2Cl2) 231.5 (26,142). m/z (CI) 414
(Mϩ1ϩ, 100), (EI) 413 (Mϩ, 20), 201 (100). HRMS Found:
Mˆ413.1813. C27H27SNO requires 413.1830.
4-Diphenylphosphinyl)-13-(4,4-dimethyloxazolin-2-yl)-
[2.2]paracyclophane 19. Pre-cooled n-butyllithium
(0.6 ml, 2.65 M, 1.59 mmol) in ether was introduced with
a syringe into a stirred solution of 11 (0.5 g, 1.30 mmol) in
dry ether (20 ml) at Ϫ78ЊC under nitrogen. The mixture was
allowed to reach room temperature and then cooled to
Ϫ42ЊC and added by a cooled cannula to a well stirred
solution of diphenylphosphinyl chloride (0.5 ml,
2.79 mmol) in ether (5 ml) at Ϫ42ЊC. The resulting mixture
was allowed to warm to room temperature, stirred overnight
and then concentrated almost to dryness. Dichloromethane
(50 ml) was added and the solution washed with brine
(50 ml). The organic fraction was dried, filtered and concen-
trated to give a yellow solid (1.112 g). Chromatography on a
short column (silica matrix 60, 35–70 m) using gradient
elution (petroleum ether (100%) to petroleum ether:ethyl
acetate (80:20)) gave two major fractions containing
4-(4,4-dimethyloxazolin-2-yl)[2.2]paracyclophane and the
desired product. Further purification using a Chromatatron
(silica gel 60 PF254, petroleum ether:ether (90:10)) gave 19
(0.341 g, 54%) as white crystals mp 174–175ЊC. dH 1.48
(3H, s, CH3), 1.59 (3H, s, CH3), 2.90 (1H, m, H-2a), 3.11
(1H, ddd, Jˆ4.0, 7.7, 12.2 Hz, H-1b), 3.43 (1H, m, H-2b),
4.21 (1H, d, Jˆ7.6 Hz, OCH), 4.39 (1H, d, Jˆ7.6 Hz,
OCH), 4.56 (1H, ddd, Jˆ2.6, 9.6, 12.2 Hz, H-1a), 5.88
(1H, dd, Jˆ7.1, 1.4 Hz, H-5), 6.57 (2H, d, Jˆ4.0 Hz),
6.65 (2H, s), 7.15 (1H, s), 7.33 (10H, m). dC (CDCl3)§
27.76, 27.80, 28.5, 34.2, 34.4, 34.8, 34.9, 35.5, 67.6
(CMe2), 78.1 (OCH2), 127.1, 128.2, 128.3, 128.4, 128.5,
128.6, 132.3, 133.2, 133.5, 133.7, 134.5, 134.9, 135.1,
136.2, 137.1, 177.2, 137.8, 137.9, 138.8, 139.2, 139.4,
141.2, 143.6, 143.8, 162.0 (CvN). dP Ϫ4.981. lmax
(CH2Cl2) 227 (27,702), 267 (13,913). nmax (cmϪ1) 1639
(CvN). m/z (EI) 489 (Mϩ, 47%), 433 (42), 288 (100),
287 (44), 209 (68), 178 (64), 165 (37). HRMS Found:
Mˆ490.2293. C33H32PNO requires 490.2300.
4-Amino-13-carbomethoxy[2.2]paracyclophane 17. The
amine 15 (0.05 g, 0.156 mmol) was dissolved in toluene
(2.5 ml) and aqueous HCl (2.5 ml, 12 M) was added and
the stirred mixture was heated under reflux for 12 h. The
mixture was cooled to room temperature and methanol
(15 ml) was added. The reaction mixture was then heated
under reflux for 24 h, cooled to room temperature and
brought to pH 8–9 using 10% NaHCO3. The toluene layer
was concentrated to give pure 17 (0.0224 g, 78%) mp 180–
181ЊC. dH 2.65 (1H, ddd, Jˆ5.5, 10.7, 15.0 Hz, H-2a), 3.0–
2.8 (5H, m, 1b, H-9a, 9b, 10a, 10b), 3.07 (1H, ddd, Jˆ2.7,
9.7, 13.8 Hz, H-2b), 3.81 (3H, s, CO2CH3), 4.22 (1H, ddd,
Jˆ5.5, 9.7, 14.3 Hz, H-1a), 5.36 (1H, d, Jˆ1.7 Hz, H-5),
6.10 (1H, dd, Jˆ1.7, 7.7 Hz, H-7), 6.26 (1H, d, Jˆ7.7 Hz,
H-8), 6.34 (1H, d, Jˆ7.8 Hz, H-15), 6.61 (1H, dd, Jˆ1.9,
7.7 Hz, H-16), 7.17 (1H, d, Jˆ1.9 Hz, H-12). dC 32.1, 30.1
(C-1, 2), 35.2, 35.1 (C-9, 10), 52.0 (CO2CH3), 122.7, 121.3
(C-5, 7), 124.4, 127.3 (C-3, 14), 136.7, 135.7, 135.2, 134.1
(C-8, 12, 15, 16), 141.9, 140.5, 138.6 (C-6, 11, 13), 145.9
(C-4), 168.9 (CO2Me). lmax (CH2Cl2) 227 (16,467), 247
(11,830). nmax (cmϪ1) 3439, 3350 (NH2), 1693 (CvO). m/z
(EI) 281 (Mϩ, 14), 162 (4), 119 (100). HRMS Found:
Mˆ281.1404. C18H19NO2 requires 281.1416.
4-Phenylthio-13-(4,4-dimethyloxazolin-2-yl)[2.2]para-
cyclophane 18. Compound 11 (0.25 g, 0.651 mmol) was
dissolved in dry ether (10 ml) with stirring under argon.
The solution was cooled to Ϫ78ЊC and n-butyllithium
(0.85 ml, 1.30 mmol) was added by syringe and the mixture
stirred for 1.5 h during which it attained room temperature.
S-Phenylbenzene thiosulfonate (0.35 g, 1.52 mmol) in ether
(2.5 ml) was cooled to Ϫ30ЊC, and transferred by cannula
to the previously made lithium derivative of 11 also at
Ϫ30ЊC. The mixture was stirred for 5 min at Ϫ30ЊC and
then for 5 h at rt, before the addition of ether (20 ml). The
reaction mixture was washed with water (2×20 ml) and the
organic layer dried (MgSO4), filtered and concentrated.
Purification by chromatography on silica (petroleum ether:
ethyl acetate, 95:5) gave 18 as a pale yellow solid (0.14 g,
52%) mp 111–112ЊC (ex petroleum ether:ethyl acetate).
Found: C, 78.50; H, 6.31; N, 3.58%. C27H27SNO requires
Acknowledgements
We thank the EU, the British Council and the Leverhulme
Trust for support of this work.
§
The extra peaks in the 13C NMR are due to restricted rotation phenomena
as shown by variable temperature studies and by comparison with 4-di-
phenylphosphinyl[2.2]paracyclophane. These studies will be reported sepa-
rately.

7338
A. Marchand et al. / Tetrahedron 56 (2000) 7331–7338
10. Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527.
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